Isoprenylcysteine (IPC) analogs modulate heterotrimeric G-protein coupled receptor (GPCR) signaling pathways, representing a novel class of topical anti-inflammatory compounds whose action is restricted to the site of application. Studies performed in the Phase I proposal demonstrate that IPC analogs have a wide spectrum of anti-inflammatory activities with a superior safety profile to glucocorticoids. Signum's proof of concept IPC analog, AFC, inhibited erythema (redness) in a double blind, vehicle controlled cosmetic human use study. More potent IPC analogs serve as attractive drug development candidates for reducing erythema and treating rosacea. Several IPC analogs identified from Signum's screening program are attractive candidates for preclinical development. The proposed Phase II research plan will identify one lead compound and two backups for preclinical development and will establish the analytical methods, process development and formulation that are necessary. Furthermore, these studies will determine the preclinical safety profile of the lead compound by performing metabolic, pharmacokinetic, toxicology and safety pharmacology studies. Together, the data generated from these studies will allow Signum to prepare and submit an IND for treatment of rosacea. PUBLIC HEALTH RELEVANCE: Rosacea is a common, chronic cutaneous condition afflicting millions of individuals. FDA approved treatments have yielded mixed results, often leaving patients with significant levels of facial redness. Successful pharmaceutical development of IPC analog anti-inflammatories will provide an important additional, and potentially better, therapeutic option for people suffering from rosacea redness.